Vinylstannyl derivatives

ABSTRACT

Vinylstannyl derivatives and the processes for their conversion to vinyliodides, vinylbromides and vinyllithium reagents. The vinylstannyl, vinyliodides, vinylbromide derivatives and vinyllithiums are useful as intermediates for the preparation of prostaglandin analogs.

This application is a continuation-in-part of our application Ser. No.923,296, filed July 10, 1978, which in turn is a continuation-in-part ofour application Ser. No. 853,941, filed Nov. 22, 1977 now U.S. Pat. No.4,233,231.

BACKGROUND OF THE INVENTION

The prostagladins are currently of great interest because of the broadphysiological responses which they elicit in animals, including man.

Development of the potential application of both natural and syntheticprostaglandins relies upon efficient chemical synthetic methods beingavailable.

Processes for preparing prostaglandins and derivatives via a conjugateaddition process have been described in U.S. Pat. Nos. 3,965,143 and3,950,406, and Tet. Letters, No. 4, 235 (1976) and Prostaglandins, 10733 (1975).

Each of the following references utilize a hydroxy protected vinyliodidesuch as A, B or C: ##STR1## as described, among others, in U.S. Pat. No.3,962,351; U.S. Pat. No. 3,962,352; U.S. Pat. No. 3,962,353; U.S. Pat.No. 4,007,210; U.S. Pat. No. 3,932,479; U.S. Pat. No. 3,965,143; andU.S. Pat. No. 3,950,406.

Recently E. J. Corey [Journ. Org. Chem. Soc., 40, 2265 (1975)] describedthe preparation of the vinylstannane D, and more recently [Journ. Amer.Chem. Soc., 98, 222 (1976)] the vinylstannyl derivative E. ##STR2##

SUMMARY OF THE INVENTION

It is the purpose of this invention to provide novel vinylstannylcompounds as key intermediate in the conjugation addition process toproduce prostaglandin analogs. In addition, these novel vinylstannylderivatives can be utilized to provide the corresponding vinyliodides inhigh yields, thereby increasing the efficiency of the correspondingacetylene to vinyliodide conversion.

DISCLOSURE

The vinylstannyl derivatives of this invention can be prepared from thecorresponding acetylene as described in Flowsheet A. In accordance withFlowsheet A, an acetylene 1 is treated with tri-n-butylstannane in thepresence of axobisisobutyronitrile wherein R₁ ' is: ##STR3## wherein R₅is selected from the group consisting of C₄ -C₇ alkyl;

R₆ is selected from the group consisting of C₅ -C₆ alkyl;

R₇ is selected from the group consisting of C₂ -C₅ alkyl;

R₈ is methyl or ethyl;

R₁₀ is selected from the group consisting of C₁ -C₄ alkyl;

R₁₁ is selected from the group consisting of C₃ -C₆ alkyl benzyl,2-butyne, and 2-butene;

n is the integer 1 or 2;

p is the integer 1 or 2; and

q is the integer 1 or 2. ##STR4##

An alternate procedure to prepare precursors of 15-hydroxy prostanoicacids is described in FLowsheet B. In accordance with Flowsheet B, anappropriate aldehyde 3 or methyl ketone 6 is treated withE-1-lithium-2-(tri-n-butyl-stannyl)ethylene [Nesmeyanov, Dokl. Akao.Navk. S.S.R., 174, 196 .(1967); E. J. Corey, Journ. Amer. Chem. Soc.,96, 5501 (1974)] or other E lithium triloweralkylstannyl ethylenederivatives to provide the corresponding E vinylstannyl alcohol 4 and 7.Alcohols 4 or 7 are treated with an appropriate hydroxyl protectinggroup. By an appropriate hydroxyl protecting group is means a protectinggroup which: (1) can be reacted with alcohols 4 or 7 to shield thehydroxyl under conditions in which the vinyl-stannyl moiety bond is notcleaved; (2) is stable under conditions whereby the trialkyl stannyl istransformed as shown in Flowsheet C or as described herein, e.g., tofinal prostaglandin product; and (3) can be removed without degradationor transformation, of end product, e.g., under weak acid conditions toprevent degradation of prostaglandin end product. Examples of suchappropriate hydroxyl protecting groups include (CH₃)₃ SiCl or (C₂ H₅)₃SiCl, which provide the vinylstannyl ethers 5 and 8, respectively,wherein R₃ is CH₃ or C₂ H₅, R₅ and R₆ are as hereinabove defined, andR₁₂ is a moiety selected from the group consisting of: ##STR5##Additional appropriate hydroxyl protecting groups include dihydropyranwhich, under weak acid conditions, forms the tetrahydropyranylderivative of alcohol 4 or 7, and ethyl vinyl ether which, under mildacid catalysis, forms the 1-ethoxy-ethyl derivative of alcohol 4 or 7.##STR6##

The novel vinylstannyl derivatives of this invention can be utilized intwo ways.

If the hydroxyl-protected vinylstannyl derivatives 5 and 7 are treatedwith one equivalent of n-butyllithium in a solvent such astetrahydrofuran at -70° to -10° C., the corresponding vinyllithium isgenerated. These vinyllithiums can then be utilized via symmetric orasymmetric cuprate formation to provide the corresponding prostaglandinas illustrated in FLowsheet C for a 15-hydroxy prostaglandin of the E₂series, where R₁₅ is an appropriate hydroxyl protecting group and R₅ isas hereinabove defined. This process is applicable to otherprostaglandin analogs. ##STR7##

In addition, the novel vinylstannyl derivatives 2 of this invention canbe converted to the corresponding vinyliodides 9 and vinylbromides 10 bytreatment with one equivalent of iodine in an organic solvent such asether as shown in Flowsheet D or with one equivalent of bromine in anorganic solvent such as carbontetrachloride as shown by Rosenbert,Journ. Amer. Chem. Soc., 79, 2138 (1957)

These vinyliodides 9 and vinylbromides 10 are also precursors for thepreparation of prostaglandins via a conjugate addition by method knownin the art. ##STR8##

Vinylstannyl derivatives according to a specific embodiment of thisinvention are those of the formula: ##STR9## wherein R₁₄ is a loweralkyl having 1 to 6 carbon atoms; R₁₅ is an appropriate hydroxylprotecting group; and R₁₆ is a lower alkyl having from 1 to 4 carbonatoms, or alternatively, from 1 to 3 carbon atoms.

The compounds are prepared as described earlier, e.g., in accordancewith Flowsheet A wherein an appropriate trialkylstannane hydride Sn(R₁₄)₃ H is used to treat an acetylene of the formula: ##STR10##previously described) in the presence of azobisisobutyronitrile.Alternatively, these compounds may be prepared in accordance withFlowsheet B wherein an appropriate E lithium (trialkylstannyl) ethylenederivative is used to treat an appropriate aldehyde or ketone to formthe E vinylstannyl alcohol which is then treated with an appropriatehydroxyl protecting group.

Specific compounds within the above formula are those of the formula:##STR11## i.e., wherein R₁₆ is a C₂ alkyl (R₁₄, R₁₅ as earlier defined).

Other specific compounds within the foregoing formula are(E)-4-trimethylsilyloxy-4-methyl-1-tri-n-butylstannyl-1-heptene;(E)-4-trimethylsilyloxy-4-methyl-1-tri-n-butylstannyl-1-octene(4-methyl-4 (RS)-trimethylsilyloxy-oct-trans-1-enyl-tri-n-butyltin);(E)-4-trimethylsilyloxy-4-methyl-1-tri-n-butylstannyl-1-nonene; and(E)-4-trimethylsilyloxy-4-methyl-1-tri-n-butylstannyl-1-decene.

DETAILED DISCLOSURE Example 1 Preparation of 3-triethylsilyloxy-1-octyne

To a magnetically stirred solution of 50 g of 1-octyn-3-ol, 83 g ofimidazole, and 500 ml of anhydrous dimethylformamide, cooled in anice-water bath under an argon atmosphere, is slowly added 90 g ofchlorotriethylsilane. After several minutes the reaction mixture iswarmed to ambient temperature, and the progress of the reaction ismonitored by tlc (1:4/ethyl acetate:benzene). On completion, thereaction mixture is poured into 500 ml of an iced mixture of 1:1hexane-water. The organic phase is separated, washed with water andbrine, dried over sodium sulfate and concentrated in vacuo. Theresulting oil is distilled to provide 83 g (bp 70°-72° C., 0.35 mm).

Example 2 Preparation of(E)-1-tri-n-butylstannyl-3-triethylsilyloxy-1-octene

A solution of 20 g of 3-triethylsilyloxy-1-octyne, 150 mg ofazobisisobutyronitrile, and 30 ml of tri-n-butyltin hydride ismagnetically stirred un er an argon atmosphere at 140° C. for 2 hours,(EXOTHERMIC), then cooled to ambient temperature. The excess tin hydrideis removed by distillation (˜70°/1.0 mm). The residue is purified bydistillation to provide 36.5 g of the oil (bp 165° C. at 0.05 mm).

Example 3 Preparation of 1-octyn-4-ol

A suspension of 24.3 g (1.0 mole) of magnesium in 90 ml of dry ether isstirred at room temperature under nitrogen with 100 mg of mercuricchloride. The reaction is initiated by the addition of 2 ml of propargylbromide and maintained by the dropwise addition of a solution of 119.5 g(1.0 mole) of propargyl bromide and 107.7 g. (1.25 mole) ofvalenaldehyde in 300 ml of dry ether. While the initial reaction isquite vigorous and is maintained at 30° C. only by cooling in an icebath it may become necessary to heat the mixture to reflux temperatureafter about a third of the ether solution is added in order to maintainthe reaction. After the addition is complete the reaction mixture isrefluxed until most of the magnesium is dissolved (several hours) andthe reaction mixture is decanted from excess magnesium into 1500 ml ofstirred ice-cold ammonium chloride solution. The ether layer isseparated and the aqueous layer is extracted three times with 300 mlportions of ether. The combined ether extract is washed with saturatedsodium chloride solution, dried over magnesium sulfate and filtered.Evaporation of the ether under vacuum leaves about 115 g of yellow oil,which is distilled through a 15 cm Vigreaux column at 18 mm. Thefraction boiling at 81°-82° C. is collected (36 g) and thehigher-boiling and lower-boiling distillates may be redistilled to yieldadditional product. The infrared absorption spectrum shows at most atrace of allene (5.1μ) and gas-liquid partition chromatography shows apurity of about 98% for the main fraction.

Examples 4-17b

The product 1-alkyn-4-ols of Table I below are prepared by treatment ofthe aldehydes and ketones listed in Table I with propargyl magnesiumbromide by the procedure described above in Example.

                  TABLE I                                                         ______________________________________                                        Example                                                                              Starting Aldehyde                                                                           Product 1-alkyn-4-ol                                     ______________________________________                                         4     n-hexaldehyde 1-nonyn-4-ol                                              5     n-heptaldehyde                                                                              1-decyn-4-ol                                              6     n-butyraldehyde                                                                             1-heptyn-4-ol                                             7     2-octanone    4-methyl-4-hydroxy-1-decyne                               8     trans-2-hexenal                                                                             4-hydroxy-5-trans-nonen-1-yne                             9     2,2-dimethylhexanal                                                                         5,5-dimethyl-4-hydroxy-1-nonyne                          10     2-heptanone   4-methyl-4-hydroxy-1-nonyne                              11     2,2-dimethylpentanal                                                                        5,5-dimethyl-4-hydroxy-1-octyne                          12     2-methylpentanal                                                                            5-methyl-4-hydroxy-1-octyne                              13     2-methylhexanal                                                                             5-methyl-4-hydroxy-1-nonyne                              14     2-hexanone    4-hydroxy-4-methyl-1-octyne                              15     trans-3-hexen-2-one.sup.a                                                                   4-hydroxy-4-methyl-5-trans-                              octen-1-yne                                                                   16     trans-2-pentenal.sup.b                                                                      4-hydroxy-5-trans-octen-1-yne                            17     trans-2-heptenal.sup.b                                                                      4-hydroxy-5-trans-de-en-1-yne                             17a   cyclohexanone 1-(2-propynyl)-cyclohexan-1-ol                            17b   cyclopentanone                                                                              1-(2-propynyl)-cyclopenton-1-ol                          ______________________________________                                    

Example 18 Preparation of 4-benzoyloxy-1-octyne

To a stirred solution of 63 g (0.50 moles) of 1-octyn-4-ol (Example 93)in 500 ml of pyridine is added 77 g (0.55 moles) of benzoyl chloride.After stirring for 1.5 hours the mixture is treated with 10 ml of water,allowed to stand for 15 minutes, and concentrated. A solution of theresidue in ether is washed successively with ice-cold hydrochloric acid,water, sodium bicarbonate solution, and brine. The solution is driedover magnesium sulfate, filtered through Celite, and concentrated togive an oil, λmax. 3240 (terminal acetylene) and 1730 cm⁻¹ (benzyloxygroup).

Example 19 Stereoselective Hydrolysis of Racemic 4-benzoyloxy-1-octyneby Rhizopus arrhizus

An agar slant of R. arrhizus (MUMF 1638) is used to inoculate 7 shakeflasks (250 ml Erlenmeyer). Each flask contains 50 ml of a mediumconsisting of 2% Edamine, 2% glucose, and 0.72% corn steep liquor inwater with pH adjusted to 7.0. A total of 14 such flaks are incubated ona rotary shaker at 28° C. After 72 hours incubation, 50 mg of racemic4-benzoyloxy-1-octyne (Example 18) in 0.1 ml of acetone is added to eachflask. After 28 hours the flasks are harvested and worked up byextraction of the whole mash with an equal volume of chloroform. Thecombined extracts are dried over magnesium sulfate and concentrated. Theresulting oil is chromatographed on a column of silica gel with hexaneprogressively enriched in ethyl acetate.

From fractions 3-6 is obtained 150 mg of colorless oil, identical to4-benzoyloxy-1-octyne, [α]_(D) ²⁵ =5±1.0° (C=0.91, ethyl acetate). Thiscompound has the (S)-configuration.

From fractions 13-20 is obtained 75 mg of colorless oil, identical to4-hydroxy-1-octyne, [α]_(D) ²⁵ =-17±1.0° (C=0.77, ethyl acetate). Thiscompound has the (R)-configuration.

The strain of R. arrhizus utilized in this experiment is a higher funguswhich grows steadily on a variety of artificial media at 20°-25° C. Inthis study of the taxonomic aspects of the culture, Petri dishes ofpotato-dextrose, malt extract, and cornmeal agars were inoculated andincubated at ambient room temperature for 10 days. Observations ofcultural and morphological characteristics are recorded in thedescription below:

Colonies on Petri dishes of potato-dextrose agar growing rapidly,covering the agar surface in 3-5 days and producing a thick, loose matof grayish mycelium. Colony surface characterized by abundant blacksporangia. Colony reverse grayish white. Colonies on malt extract agargrowing rapidly, covering the agar surface in 3-5 days. Mycelial matthick, grayish-yellow. Colony surface becoming brownish-black frommasses of sporangia. Colony reverse yellowish. Colonies on cornmeal agarvery thin, whitish; spreading across agar surface. Cultures transparentwith relatively few sporangia produced. Visibility of micromorphology isgood on this medium. Rhizoids produced sparingly along stoloniferoushyphae. Generally two to three sporangiophores arose from rhizoids.Walls of sporangiophores oliv brown, 14.0-20.0 μm in width at base,tapering slightly to apex; 0.5-1.5 mm in length. Sporangiophoresterminated by spherical sporangia, 130-225 μm in diameter. Columellaehemispherical, 3-50 μm high by B 50-70 μm wide. Spores brownish whenmature, 6.0-8.5 μm ×4.5-6.0 μm. Spore walls conspicuously marked bylongitudinal striations.

Example 20 Preparation of (S)-4-hydroxy-1-octyne

A solution of 1.15 g (5.0 mmoles) of (S)-4-benzoyloxy-1-octyne (Example19) and 1.40 g (25 mmoles) of potassium hydroxide in 50 ml of 10:1methanol-water is allowed to stand at toom temperature for 24 hours. Thebulk of the methanol is evaporated at room temperature, and the mixtureis extracted with ether. The extract is washed with brine, dried overmagnesium sulfate, and evaporated to give a colorless oil, identical to4-hydroxy-1-octyne [α]_(D) ²⁵ =+17±1.0° (C=0.77, ethyl acetate). Thiscompound has the (S)-configuration.

Examples 21-40

Treatment of the hydroxy-acetylenes of Table II with the indicatedtriloweralkylchlorosilane according to the procedure of Example 1followed by treatment of the resulting silylether withtri-n-butylstannane by the procedure of Example 2 is productive of thesilyloxyvinylstanne of the Table.

                                      TABLE II                                    __________________________________________________________________________    Example                                                                            Starting Hydroxy Acetylene                                                                  Silylchloride                                                                        Product silyloxyvinylstannane                       __________________________________________________________________________    21   Ex. 3         TES    (E)-4-triethylsilyloxy-1-tri-n-                                               butylstannyl-1-octene                               22   Ex. 5         TES    (E)-4-triethylsilyloxy-1-tri-n-                                               butylstannyl-1-1-decene                             23   Ex. 6         TES    (E)-4-triethylsilyloxy-1-tri-n-                                               butylstannyl-1-heptene                              24   Ex. 4         TES    (E)-4-triethylsilyloxy-1-tri-n-                                               butylstannyl-1-nonene                               25   Ex. 7         TMS    (E)-4-methyl-4-trimethylsilyloxy-                                             tri-n-butylstannyl-1-decene                         26   Ex. 8         TES    (E)-4-triethylsilyloxy-1-tri-n-                                               butylstannyl-1,5-trans-nonadiene                    27   Ex. 9         TMS    (E)-4-trimethylsilyloxy-5,5-di-                                               methyl-1-tri-n-butylstannyl-1-                                                nonene                                              28   Ex. 10        TMS    (E)-4-methyl-4-trimethylsilyloxy-                                             1-tri-n-butylstannyl-1-nonene                       29   Ex. 11        TMS    (E)-4-trimethylsilyloxy-5,5-dimethyl-                                         1-tri-n-butylstannyl-1-octene                       30   Ex. 12        TES    (E)-4-triethylsilyloxy-5-methyl-1-                                            tri-n-butystannyl-1-octene                          31   Ex. 13        TES    (E)-4-triethylsilyoxy-5-methyl                                                1-tri-n-butylstannyl-1-nonene                       32   Ex. 14        TMS    (E)-4-trimethylsilyloxy-4-methyl-                                             1-tri-n-butylstannyl-1-octene                       33   Ex. 15        TMS    (E)-4-trimethylsilyloxy-4-methyl-                                             1-tri-n-butylstannyl-1,5-trans-                                               octadiene                                           34   Ex. 16        TES    (E)-4-triethylsilyloxy-1-tri-n-                                               butylstannyl-1,5-trans-octadiene                    35   Ex. 17        TES    (E)-4-triethylsilyloxy-1-tri-n-                                               butylstannyl-1,5-trans-decadiene                    36   Ex. 19        TES    (E)-4(R)-triethylsilyloxy-1-tri-n-                                            butylstannyl-1-octene                               37   Ex. 20        TES    (E)-4(S)--triethylsilyloxy-1-tri-n-                                           butylstannyl-1-octene.                              38   1-decyne-3-ol U.S. Pat.                                                                     TES    (E)-3-triethylsilyloxy-1-tri-n-                          No. 3,873,601 Ex. 129                                                                              butylstannyl-1-decene                               39   4-methyl-1-heptyne-3-ol U.S.                                                                TES    (E)-3-triethylsilyloxy-4-methyl-                         Pat. No. 3,873,607 Ex. 132                                                                         1-tri-n-butylstannyl-1-octene                       40   4-ethyl-1-octyne-3-ol.sup.1                                                                 TES    (E)-3-triethylsilyloxy-4-ethyl-                          U.S. Pat. No. 3,873,607 Ex. 130                                                                    1-tri-n-butylstannyl-1-octene                        40a Ex. 17a       TMS    1-(E-3-tri-n-butylstannyl-2-                                                  propenyl)-1-trimethylsilyloxy-                                                cyclohexane                                          40b Ex. 17b       TMS    1-(E-3-tri-n-butylstannyl-2-                                                  propenyl)-1-trimethylsilyloxy-                                                cyclopentane                                        __________________________________________________________________________

Example 41 Preparation of 3-tetrahydropyranyloxy-1-propyne

To a stirred solution of 112 g (2.0 mol.) of 3-hydroxy-1-propyne and 260g (3.0 mol.) of dihydropyran in 1.20 liters of methylene chloride cooledto 0° C. in an ice bath, is added a solution of 20 mg ofpara-toluenesulfonic acid in 100 ml of methylene chloride, dropwise. Thereaction mixture is stirred at 0° C. for one-half hour, and at ambienttemperature for one hour. It is then poured into 200 ml of a 5% solutionof sodium bicarbonate, the organic phase is separated, the aqueous phaseextracted with 100 ml of methylene chloride, the combined organic phaseswashed with 100 ml of a solution of brine, dried over sodium sulfate,and evaporated under vacuum (12 mm) at 45° C. to give 300 g of crudeproduct, which is purified by fractional distillation, bp 71°-73° C. (14mm) to yield 250 g (89%) of a liquid.

Example 42 Preparation of3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne

To a stirred -20° C. solution of 125 g (0.89 mol.) of3-tetrahydropyranyloxy-1-propyne (Example 41) in 450 ml of ether, undera nitrogen atmosphere, is added dropwise, over one hour, a solution of45 ml (0.89 mol.) of 2.0N n-butyllithium in hexane. After 150 ml of dryether is added and the mixture is stirred at -20° C. for 30 minutes, asolution of 98 g (0.89 mol.) of trimethylchlorosilane in 73 ml of etheris added dropwise. Stirring is continued for 30 minutes at -20° C. andat ambient temperature for 18 hours. The reaction mixture is againcooled to -20° C., and a solution of 90 ml of acetic acid in 300 ml ofether is added dropwise, followed by 90 ml of water. It is then dilutedwith 500 ml of water, and extracted 3 times with 300 ml of 5% sodiumbicarbonate solution. The organic phase is separated, washed with 500 mlof a saturated brine solution, dried over sodium sulfate, and evaporatedat 40° C. under vacuum (12 mm). The crude product is fractionallydistilled, bp 120°-125° C. (18 mm), to yield 120 g of an oil.

Example 43 Preparation oferythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne

To a stirred -78° C. solution of 62 ml (124 mmol.) of a 2.0M solution ofn-butyllithium in hexane and 50 ml of dry tetrahydrofuran, under anitrogen atmosphere is added dropwise, a solution of 24 g (113 mmol.) of3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne (Example 42) in 35 mlof tetrahydrofuran. This red solution is stirred one hour at -78° C.,tehn a freshly prepared solution of zinc iodide (135 mmol.) in 125 ml oftetrahydrofuran [F. Mercier, R. Eqsztein, and S. Holand, Bull. Soc.Chim. Franc, 2, 690 (1972)] is added dropwise at -78° C. until themixture turns yellow. After stirring an additional hour at -78° C., asolution of 21 g (250 mmol.) of n-valeraldehyde in 35 ml oftetrahydrofuran is added dropwise and the reaction mixture stirred forone hour at -78° C. and 18 hours at ambient temperature. It is thencooled to 0° C. and a solution of 12 ml of acetic acid in 65 ml of etheris added dropwise, followed by 75 ml of ice-water. The phases areseparated and the aqueous phase is extracted twice with ether. Thecombined organic phases are washed 3 times with saturated sodiumbicarbonate solution, until the last wash is basic, then with asaturated brine solution, dried over sodium sulfate, and evaporated togive 40 g of yellow oil. The crude product may be purified on a 4"×40"dry column of alumina, and eluted with chloroform. I.R.: neat; 3550(OH), 2200 (C.tbd.C), 840, 750[(CH₃)₃ Si], cm⁻¹.

Example 44 Preparation oferythro-3,4-dihydroxy-1-trimethylsilyl-1-octyne

A solution of 19.6 g (0.066 mol) ofd,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-oxtyne(Example 43) in 55.5 ml of ethanol, 22.2 ml of acetic acid, and 22.2 mlof water is heated at reflux for 3 hours. The cooled mixture is taken todryness and evaporated twice with benzene. The residue is taken up inhexane, washed 3 times with saturated potassium bicarbonate solution,dried with magnesium sulfate, and evaporated to give 17.0 g of crudeproduct. IR: neat, 3500-3400, broad (two OH)

Example 45 Preparation oferythro-3,4-isopropylidenedioxy-1-trimethylsilyl-1-octyne

To a stirred solution of 17.0 g (79.5 mmol.) of cruded,1-erythro-15,16-dihydroxy-1-trimethylsilyl-1-octyne (Example 44) is33.6 ml of 2,2-dimethoxy propane at 0° C., is added 0.05 ml of 60%perchloric acid. After 30 minutes at ambient temperature, the mixture isshaken with 50 ml of hexane and 25 ml of saturated sodium bicarbonatesolution. The hexane phase is separated, dried with magnesium, sulfate,and evaporated to give 19.0 g of crude product.

Example 46 Preparation of erythro-3,4-isopropylidenedioxy-1-octyne

A mixture of 19.0 g (75.0 mmol.) of cruded,1-erythro-3,4-isopropylidenedioxy-1-trimethylsilyl-1-octyne (Example45) with 95 ml of methanol and 3.0 g of potassium carbonate is refluxedfor one hour. The mixture is cooled and evaporated at 50° C. (13 mm),taken up in 250 ml of benzene, and washed with 100 ml of water. Thewater is saturated with salt, the organic phase separated, dried withmagnesium sulfate, and evaporated to give 12 g of crude product.Fractional distillation yields 7.0 g of the subject compound as acolorless oil, bp 103°-106° C. (13 mm).

IR: neat; 3300 sharp (H-C C), 2100 (C.tbd.C), 780 (erythroconfiguration) cm⁻¹

nmr: CDCl₃ : TMS; 4.75 (dd. 1, C C--CH--CH, J=2 Hz, J=5 Hz, 4.10 (m, 1,C C--CH--CH--CH₂, 2.5 (d, 1, H--C C--CH), 1.9-1.2 (m, 14, alkyl), 0.90(m, 3H, CH₂ CH₃).

Example 47 Preparation oferythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A solution of 3.0 g (13.2 mmol.) oferythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne isheated at 100° C. for 15 hours with 3 ml of acetic anhydride and 10 mlof pyridine. The mixture is evaporated to dryness, dissolved in ether,washed with sodium bicarbonate solution and water. The organic phase isdried over magnesium sulfate and evaporated to give 2.5 g of the subjectcompound as an oil.

IR: neat; 2200 (C.tbd.C), 1730 (C.tbd.O), 830, 760 [(CH₃)₃ Si], cm⁻¹.

Example 48 Preparation ofd,1-erythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A solution of 2.5 g (7.4 mmol.) oferythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne(Example 47) in ethanol, acetic acid, and water is heated at 100° C. for3 hours. After workup, the crude product is chromatographed on a7/8"×22" dry column of silica gel, and eluted with chloroform to give1.0 g of a yellow oil.

IR: neat; 3500 (OH), 1730 (C═O), cm⁻¹.

Example 49 Preparation oferythro-3-paratoluenesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

To a solution of 7.5 g (41.0 mmol.) oferythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 48) in41 ml of dry pyridine is added 11.0 g (58 mmol.) of para-toluenesulfonylchloride and the resulting solution is stirred at 25° C. for 15 hours.The mixture is then warmed at 40° C. for one hour, and after cooling,partitioned between 500 ml of diethyl ether and 100 ml of 1.0Nhydrochloric acid. The organic phase is washed three times with 100 mlof 1.0N hydrochloric acid, once with dilute sodium bicarbonate solution,dried over magnesium sulfate, and evaporated under reduced pressure togive an oil. The crude product is purified on a 2"×24" dry column ofsilica gel, and eluted with chloroform to yield a yellow oil.

IR: neat; 1730 (C═O), 1595 (aromatic) cm⁻¹.

Example 50 Preparation ofthreo-3-hydroxy-4-acetyloxy-1-trimethyl-silyl-1-octyne

A mixture of 15.5 g (39.0 mmol.) oferythro-3-para-toluenesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne(Example 49), 5.0 g of calcium carbonate, 25 ml of water and 250 ml oftetrahydrofuran is refluxed with stirring for 4 days. The mixture iscooled, 100 ml of water added and the organic phase separated. Theaqueous phase is extracted with ether, the combined organic phases driedwith magnesium sulfate, and evaporated. The crude product ischromatographed on a 3"×30" dry column of silica gel, and eluted withchloroform to give 7.0 g of an oil.

IR: neat; 3500, (OH), cm⁻¹.

Example 51 Preparation of threo-3,4-dihydroxy-1-octyne

A solution of 7.0 g (28 mmol.) ofthreo-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 50) in 50ml of methanol is stirred at room temperature for 24 hours with asolution of 6.3 g (112 mmols) of potassium hydroxide in 50 ml of water.The mixture is extracted twice with hexane, washed with 0.5Mhydrochloric acid, brine, and dried with magnesium sulfate. Afterevaporation, the subject compound is obtained as a yellow oil.

IR: neat, 2500 broad (2-OH), cm⁻¹.

Example 52 Preparation of threo-3,4-isopropylidenedioxy-1-octyne

In the manner of Example 45, treatment of a solution ofthreo-3,4-dihydroxy-1-octyne (Example 51) in dimethoxypropane with 60%perchloric acid, the fractional distillation (12 mm) is productive ofthe subject compound as a colorless oil, containing 15% ofd,1-erthro-3,4-isopropylidenedioxy-1-octyne (Example 60), as animpurity.

IR: neat; 810 (threo configuration). nmr: CDCl₃ : TMS; 4.2 (dd, 1,--C.tbd.C--CH--, J's--2H_(z), 6H_(z)), 4.1-3.9 (m, 1, --C C--CH--CH--CH₂--), 2.5 (d, 1, H--C C--, J=2H_(z)), 1.9-1.2 (m, 14, alkyl), 0.90 (m,3H, CH₂ --CH₃).

Example 53 Preparation oferythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne

Alkaline hydrolysis ofd,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne(Example 43) by the procedure of Example 46 is productive of the subjectcompound.

Example 54 Preparation oferythro-3-tetrahydropyranyloxy-4-methoxy-1-octyne

To a stirred slurry of 6.0 g (150 mmol.) of a 60% oil dispersion ofsodium hydride and 96 g of iodomethane, under an argon atmosphere, isadded 700 ml of dry tetrahydrofuran. The stirred mixture is cooled to-20° C. and a solution of 30 g (133 mmol.) oferythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne (Example 53), is addeddropwise, followed by 0.1 ml of methanol. The mixture is stirred atambient temperature for 24 hours, 10 ml of methanol is added, andevaporated. The residue is taken up in ether, washed 3 times with water,dried over magnesium sulfate, and evaporated. The crude product ispurified by fractional distillation to yield 16.3 g of a colorless oil,bp 137°-14° C. (12 mm).

Examples 55-59

By the method of Example 43 reactions of1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne with n-butyllithiumand subsequent treatment with the aldehydes listed in Table III, below,provides thed,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkynesof the table.

                  TABLE III                                                       ______________________________________                                               Starting  Product erythro-3-tetrahydropyranyloxy-                      Example                                                                              Aldehyde  4-hydroxy-1-trimethylsilyl-1-alkyne                          ______________________________________                                        55     n-buanal  erythro-1-trimethylsilyl-3-tetrahydro-                                        pyranyloxy-4-hydroxy-1-heptyne                               56     n-hexanal erythro-1-trimethylsilyl-3-tetrahydro-                                        pyranyloxy-4-hydroxy-1-nonyne                                57     n-heptanal                                                                              erythro-1-trimethylsilyl-3-tetrahydro-                                        pyranyloxy-4-hydroxy-1-decyne                                58     4-methyl-n-                                                                             erythro-1-trimethylsilyl-3-tetrahydro-                              pentanal  pyranyloxy-4-hydroxy-7-methyl-1-octyne                       59     2-trans-n-                                                                              erythro-1-trimethylsilyl-3-tetrahydro-                              pentenal  pyranyloxy-4-hydroxy-5-trans-octen-1-yne                     ______________________________________                                    

Examples 60-66

Hydrolysis of the 3-tetrahydropyranyloxy group of thed,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkyneslisted in Table IV below by the method describe in Example 44, followedby conversion of the resultingerythro-1-trimethylsilyl-3,4-dihydroxy-1-alkyne to the correspondingd,1-erythro-1-trimethylsilyl-3,4-isopropylidenedioxy-1-alkyne bytreatment with dimethoxypropane in the presence of perchloric acid bythe method described in Example 45 followed by desilylation to thecorresponding erythro-3,4-isopropylidenedioxy-1-alkyne by the procedureof Example 46 followed by treatment with tri-n-butylstannane accordingto this procedure of Example 2 is productive of the vinylstannylderivatives of Table IV.

                                      TABLE IV                                    __________________________________________________________________________         Starting d,1-erythro-1-trimethylsilyl-                                        silyl-3-tetrahydropyranyloxy-4-hydroxy-                                                          Product erythro-1-iodo-3,4-iso-                       Example                                                                            1-alkyne of Example                                                                              propylidenedioxy-trans-1-alkene                       __________________________________________________________________________    60   53                 erythro-1-tri-n-butylstannyl-3,4-                                             isopropylidenedioxy-trans-1-hep-                                              tene                                                  61   54                 erythro-1-tri-n-butylstannyl-3,4-                                             isopropylidenedioxy-trans-1-nonene                    62   55                 erythro-1-tri-n-butylstannyl-3,4-                                             isopropylidenedioxy-trans-1-decene                    63   56                 erythro-1-tri-n-butylstannyl-3,4-                                             isopropylidenedioxy-7-methyl-trans-                                           1-octene                                              64   57                 erythro-1-tri-n-butylstannyl-3,4-                                             isopropylidenedioxy-trans,trans-                                              1,5-octadiene                                         65   46                 erythro-1-tri-n-butylstannyl-3,4-                                             isopropylidenedioxy-1-octene                          66   52                 threo-1-tri-n-butylstannyl-3,4-                                               isopropylidenedioxy-1-octene                          __________________________________________________________________________

Examples 67-71

Acetylation of the 4-hydroxy group of theerythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkyneslisted in Table V below by the method described in Example 47, followedby hydrolysis of the resultingerythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-acetyloxy-1-alkynes tothe correspondingerythro-1-trimethylsislyl-3-hydroxy-4-acetyloxy-1-alkynes by the methodof Example 49, followed by epimerization tothreo-1-trimethylsilyl-3-hydroxy-4-acetyloxy-1-alkynes by the method ofExample 50 followed by hydrolysis by the method of Example 51 to givethreo-3,4-dihydroxy-1-alkynes are converted to the correspondingthreo-3,4-isopropylidenedioxy-1-alkynes by treatment withdimethoxypropane in the presence of perchloric acid by the methoddescribed in Example 52 followed by treatment with tri-n-butylstannaneby the procedure of Example 2 is productive of the threo vinylstannylderivatives.

                  TABLE V                                                         ______________________________________                                               Starting erythro-1-tri-                                                       methylsilyl-3-tetra-                                                          hydroxypyranyloxy-4-                                                                        Product threo-1-tri-n-butylstannyl-                             hydroxy-1-alkyne                                                                            3,4-isopropylidenedioxy-trans-1-                         Example                                                                              of Example    alkene                                                   ______________________________________                                        67     53            threo-1-tri-n-butylstannyl-3,4-iso-                                           propylidenedioxy-trans-1-heptene                         68     54            threo-1-tri-n-butylstannyl-3,4-iso-                                           propylidenedioxy-trans-1-nonene                          69     55            threo-1-tri-n-butylstannyl-3,4-iso-                                           propylidenedioxy-trans-1-decane                          70     56            threo-1-tri-n-butylstannyl-3,4-iso-                                           propylidenedioxy-7-methyl-trans-                                              1-octene                                                 71     57            threo-1-tri-n-butylstannyl-3,4-iso-                                           propylidenedioxy-1,5-trans; trans-                                            1-octadiene                                              ______________________________________                                    

Examples 72-74

Treatment of the alkynes of Table VI with tri-n-butylstannane by theprocedure of Example 2 is productive of the vinylstannyl derivatives ofthe Table.

                  TABLE VI                                                        ______________________________________                                        Example                                                                              Starting Alkyne                                                                           Product Vinylstannyl Derivative                            ______________________________________                                        72     46          erythro-1-tri-n-butylstannyl-3,4-iso-                                         propylidenedioxy-1-octene                                  73     52          threo-1-tri-n-butylstannyl-3,4-isoprop-                                       lidenedioxy-1-octene                                       74     54          erythro-1-tri-n-butylstannyl-3-tetra-                                         hydropyranyloxy-4-methoxy-1-octene                         ______________________________________                                    

Example 75 Preparation of(E)-1-tri-n-butylstannyl-3-methyl-3-trimethylsilyloxy-1-octene

To a solution of 3 g of trans-1,2-bis(tri-n-butylstannyl) ethylene in 15ml of dry tetrahydrofuran at -78° C. is added 2.5 ml of 2.1Mn-butyllithium. After allowing the solution to warm to -40° C., thesolution is transferred to another flask containing 550 mg of 2heptanone in 10 ml of tetrahydrofuran. After warming to roomtemperature, the reaction mixture is poured into saturated aq. ammoniumchloride and extracted with hexanes. Concentration of the hexanesprovides (E)-1-tri-n-butylstannyl-3-methyl-1-octene-3-ol.

The vinylstannane is treated with imidazole, and chlorotrimethylsilanein dimethylformamide by the procedure of Example 1 to provide(E)-1-tri-n-butylstannyl-3-methyl-3-trimethylsilyloxy-1-octene as anoil.

EXAMPLES 76-88

Treatment of the ketones and aldehydes of Table VII by the procedure ofExample 75 with trans-1-lithio-2-tri-n-butylstannyl ethylene followed bytreatment of the resulting vinylstannylalcohol with the indicatedtrialkylchlorosilane by the procedure of Example 2 is productive of thevinylstannylsilyloxy products of the Table.

                                      TABLE VII                                   __________________________________________________________________________         Starting Ketones                                                         Example                                                                            and Aldehydes  Product (Stannyl Derivative)                              __________________________________________________________________________    76   2-octanone                                                                             TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-3-methyl-3-trimethyl-                                silyloxy-1-nonene                                         77   2-nonanone                                                                             TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-3-methyl-3-trimethyl-                                1-decene                                                  78   2,2-dimethyl-1-                                                                        TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-4,4-dimethyl-3-trimethyl-             hexanol U.S.   silyloxy-1-octene                                              Pat. No. 3,873,607                                                       79   3,3-dimethyl-1-                                                                        TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-5,5-dimethyl-3-trimethyl-             hexanol U.S.   silyloxy-1-octene                                              Pat. No. 3,873,607                                                       80   4-ethyl-1-oct-                                                                         TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-4-ethyl-3-trimethylsilyl-             yne-3-ol U.S.  oxy-1-octene                                                   Pat. No. 3,873,607                                                       81   4-methyl-1-hep-                                                                        TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-4-methyl-3-trimethylsilyl-            tyne-3-ol U.S. oxy-1-heptene                                                  Pat. No. 3,873,607                                                       82   2,2-trimethyl-                                                                         TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-4,4-trimethylene-3-trimethyl-                        2                                                              enehexaldehyde silyloxy-1-octene                                              Bel. Pat 843,679                                                         83   2,2-trimethyl-                                                                         TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-4,4-trimethylene-3-trimethyl-         eneoctaldehyde silyloxy-1-decene                                              Bel. Pat 843,679                                                         84   2,2-trimethyl-                                                                         TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-4,4-trimethylene-3-tri-               ene-3-phenyl-  methylsilyloxy-5-phenyl-1-pentene                              propionylalde-                                                                hyde Bel. Pat                                                                 843,679                                                                  85   2,2-trimethyl-                                                                         TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-4,4-trimethylene-3-tri-               enehex-4-yn-1- methylsilyloxy-6-yn-1-octene                                   ol Bel. Pat                                                                   843,679                                                                  86   2,2-trimethyl-                                                                         TMS--Cl                                                                             (E)-1-tri-n-butylstannyl-4,4-trimethylene-3-tri                enehex-4-dis-en                                                                              methylsilyloxy-6-cis-1-octadiene                               1-ol Bel. Pat                                                                 843,679                                                                  87   cyclohexanone                                                                          TMS--Cl                                                                             1-[(E)-2-tri-n-butylstannylethylene)]-1-trimethyl-                            silyloxy-cyclohexane                                      88   cyclopentanone                                                                         TMS--Cl                                                                             1-[(E)-2-tri-n-butylstannylethylene)]-1-trimethyl-                            silyloxy-cyclopentane                                     __________________________________________________________________________

Example 89 Conversion of(E)-1-tri-n-butylstannyl-4-triethylsilyloxy-1-octene to(E)-1-iodo-4-triethylsilyloxy-1-octene and (E)-1-iodo-4-hydroxy-1-octene

To a solution of E-1-tri-n-butystannyl-4-triethylsilyloxy-1-octene (11g) in 200 ml ether is added 0.9 equivalents of iodine in one portion.After 25 minutes the color of the iodine has disappeared. An additional0.1 equivalents of iodine is added in portions until the iodine colorpersists. The ether is removed in vacuo to provide(E)-1-iodo-4-triethylsilyloxy-1-octene. This residue is placed on asilica-gel column (240 g SilicAR CC-7) packed in hexane. A literfraction of hexane contains 7.5 g of mostly tri-n-butylidostannane. A500 ml elution of benzene gives only a small amount of material. Anelution with 600 ml of ether provides 7.0 g of 1-iodo-4-hydroxy-1-octeneas an oil.

Example 90 Preparation of(E)-1-tri-n-butylstannyl-3-(2-tetrahydropyranyloxy)-1-octene

A mixture of bis(tri-n-butylstannyl) oxide (42.5 g 71.3 mmol.) andpolymethylhydrogen siloxane (9.5 g) is stirred at ambient temperaturefor 30 minutes. To this mixture is added3-(2-tetrahydropyranyloxy)-1-octyne (21 g, 100 mmol.) andazobisisobutyronitrile (100 gm). The reaction mixture is warmed to 80°C. whereupon an exothermic reaction occurs. After several additionalhours at 80° C., the reaction mixture is distilled under vacuum toprovide 16.7 g of the product as an oil (bp 174°-178° C., 0.8 mm).

Example 91 Preparation of Ethyl-15-hydroxy-9-oxo-13-trans-prostenoiate

To a solution of(E)-tri-n-butylstannyl-3(2-tetrahydropyranyloxy)-1-octene (10.5 g, 21mmols) in tetrahydrofuran (8 ml) at -78° C. is added 2.4M n-butyllithium(8.75 ml; 21 mmols). After 1 hour at -78° C., a solution of copperpentyne mmol) in hexamethylphosphoramide (63 mmol) is added and thesolution is stirred at -50° C. for 10 minutes.

The cuprate solution is recooled to -78° C. and2-(6-carbethoxyheptyl)-2-cyclopentenone (U.S. Pat. No. 3,873,607) (4.77g, 20 mmols) in tetrahydrofuran (9 ml) is added. The resulting mixtureis stirred at -78° C. for 30 minutes and at -10° C. for 90 minutes.

The mixture is poured into saturated aq. ammonium chloride and stirred18 hours. The organic phase is separated and the blue aqueous phase isextracted several times with ether. The combined ether extracts arewashed with 1% sulfuric acid (100 ml), brine and dried over sodiumsulfate. The solvents are removed in vacuo to provide an oil. This oilis dissolved in a 4:2:1 solution of HOAC/THF/Water (340 ml) at 55° C.and stirred for 4 hours and then concentrated.

Purification of the residue by silica-gel chromatography to provide 2.7g of product.

EXAMPLE 92 Preparation of 11, 16-dihydroxy-9-oxo-13-trans-prostenoate

To a solution of(E)-1-tri-n-butylstannyl-4-methyl-4-trimethylsilyloxy-1-octene (Example32) (6.03 g) in tetrahydrofuran (5 ml) at -70° C. is added 2.2Mn-butyllithium (5.5 ml). The solution is warmed to -40° C. for 1 hourand to -30° C. for a further 1 hour.

In a second flask is placed copper pentyne (2.84 g),tri-n-butylphosphine (8.8 g) and ether (25 ml). After 20 minutes at roomtemperature, the cooper pentyne solution is transferred to a -78° C.vinyllithium solution.

After stirring at -78° C. for 2 hours, a solution of4-trimethylsilyloxy-2-(6-carbotrimethylsilyloxy)cyclopent-2-en-1-one(U.S. Pat. No. 3,873,607) (3.5 g) in ether (8 ml) is added via syringe.

The mixture is stirred at 78° C. for 10 minutes, at -40° C. to -50° C.for 1 hour at -40° C. to -30° C. for 50 minutes. The mixture is recooledto -50° C. and quenched with saturated aq. ammonium chloride (300 ml)and ether (150 ml).

The aqueous solution is extracted with ethyl acetate and the combinedorganic layers are dried magnesium sulfate and concentrated to an oil.

The oil is dissolved in a mixture of acetic acid (60 ml) tetrahydrofuran(30 ml) and water (15 ml) and stirred under nitrogen at room temperaturefor 30 minutes. Toluene (100 ml) is added and the mixture isconcentrated in vacuo to a viscous oil. Toluene is again added andreconcentrated to constant weight.

The residue is placed onto a column of 18 g of silica-gel and washedwith hexane. The hexanes fraction will give about 9 g and contains noprostaglandin product. The silica-gel is flushed with ethyl acetate (200ml) to provide 5.9 g of prostaglandin materials. This 5.9 g is purifiedvia dry-column chromatography (dcc) on 860 g of silica-gel developingwater 4:1 EtOAc/Hexane containing 1% acetic acid. The product containingfraction from the dry-column is removed and extracted with ethyl acetateto provide 1.3 g of pure product and an additional 1.0 g of nearly pureproduct.

Example 93 Conversion ofE-1-tri-n-butylstannyl-3-triethylsilyloxy-1-octene (Ex. 2) toE-1-bromo-3-triethylsilyloxy-1-octene and E-1-bromo-3-hydroxy-1-octene

To a solution of 5.85 g ofE-1-tri-n-butylstannyl-3-triethylsilyloxy-1-octene (Example 2) in 6 mlof carbon tetrachloride (CCl₄) at -20° C. is added slowly a solution ofbromine (1.8 g) in 6 ml of carbon tetrachloride under nitrogen.

After the addition is complete, (a slight yellow color should persist)the solution is allowed to warm to ambient temperature and the solventsare removed in vacuo to provide E-1-bromo-3-triethylsilyloxy-1-octene.This residue is filtered through 60 g of silic-AR CC-7 and washed with300 ml of hexane. The hexane elutant is concentrated to provide 4.6 g ofmostly Bu₃ Sn-Br.

The silica-gel cake is washed with 300 ml of ether. The ether isconcentrated to provide 3.3 g of residue that is mostlyE-1-bromo-3-hydroxy-1-octene.

Example 94 Treatment of the (E)-1-tri-n-butylstannyl derivatives ofExamples 2 , 21-40b and 60-88 with iodine

Treatment with iodine, by the procedure of Example 89, followed bypurification, by the procedure of Example 89, will provide thecorresponding E-1-iodo-hydroxy and tri lower alkyl silyloxy (or otherprotected) derivatives.

Example 95 Treatment of the E-1-tri-n-butylstannyl derivatives ofExamples 21-40b and 60-88 with bromine

Treatment with bromine, by the procedure of Example 93, followed bypurification by the method of Example 93, is productive of thecorresponding E-1-bromo-3-hydroxy and E-1-bromo-4-hydroxy alkenes.

Example 96 Preparation ofE-1-tri-n-butylstannyl-3-trimethylsilyloxy-4,4-dimethyl-1-octene andZ-1-tri-n-butylstannyl-3-trimethylsilyloxy-4,4-dimethyl-1-octene

A mixture of 2 g (8.83 mmole) of3-trimethylsilyloxy-4,4-dimethyl-1-octyne [prepared from3-hydroxy-4,4-dimethyl-1-octyne U.S. Pat. No. 4,007,210 andchlorotrimethylsilane (Method of Example 1)], 10 mg ofazobisisobutyronitrile and 2.09 ml (7.9 mM) of tri-n-butylstannane isstirred in an oil bath under argon atmosphere at ambient temperature andthen the temperature is gradually raised to 130° C. The resultingsolution is stirred at 130°-135° C. for 2 hours, then cooled to furnishZ-1-tri-n-butylstannyl-3-trimethylsilyloxy-4,4-dimethyl-1-octene. Vaporphase chromatography on a 6'5% SE 30 column at an oven temperature of230° C. shows a peak at retention time of 5.2 minutes. Further treatmentof this solution containing the Z isomer with additionaltri-n-butylstannane (3-4 mmole) and azobisisobutyronitrile (20 mg) at130°-135° C. for 4-hour furnishesE-1-tri-n-butylstannyl-3-trimethylsilyloxy-4,4-dimethyl-1-octene. Vaporphase chromatography shows a peak at retention time of 4.7 minutes.

Example 97

A solution of 40.0 g of 4-triethylsilyloxy-4-methyl-1-heptyne, 180 mg ofazobisisobutyronitrile, and 50 ml of tri-n-butyltin hydride is stirredunder an argon atmosphere at 130° C. for 2 hours, then allowed to coolto ambient temperature. The excess tin hydride is removed bydistillation and the residue purified to provide 63.5 g of the(E)-4-triethylsilyloxy-4-methyl-1-tri-n-butylstannyl-1-heptene (b.p.160°-88° C. at 0.6 mm).

Example 98

To a stirred mixture of 33.96 g of 4-methyl-4-trimethylsilyloxy nonyneand 150 mg of azobisisobutyronitrile at ambient temperature under argonwas added 41 ml of tri-n-butyltin hydride via syringe. The mixture wasslowly heated in an oil bath, with a rapid exothermic reaction to 120°C. taking place as the temperature reached 60° C. Heating to 130°-135°C. continued for one hour. The product was then allowed to cool and wasthen distilled to provide 74.5 g of(E)-4-methyl-4-trimethylsilyloxy-1-tri-n-butylstannyl-1-nonene (b.p.162°-164° C. at 0.15-0.30 mm).

Example 99

A solution of 30 g of 4-methyl-4-trimethylsilyloxy-1-decyne, 150 mg ofazobisisobutyronitrile, and 35 ml of tri-n-butyltin hydride wasmagnetically stirred under an argon atmosphere at 130°-135° C. for about2 hours (exothermic), then cooled to ambient temperature. The productwas distilled to provide 60 g of(E)-4-methyl-4-trimethylsilyloxy-1-tri-n-butylstannyl-1-decene (b.p.156°-158° at 0.03 mm).

Example 100

To a mixture of 22.32 g of 4-methyl-4-trimethylsiloxy-1octyne and 105 mgof azobisisobutyronitrile was added 27.87 ml of tri-n-butyltin hydride.The mixture was heated and stirred under a nitrogen atmosphere at125°-130° C. for 3 hours, and cooled to ambient temperatures. Themixture was then vacuum distilled to remove excess tin hydride andpurified (150°-160° C./0.1-0.6 mm) to obtain 7 g of(E)-4-methyl-4-trimethyl-silyloxy-1-tri-n-butystannyl-1-octene.

What is claimed is:
 1. A compound of the formula: ##STR12## wherein R₁₄is lower alkyl having 1-6 carbon atoms; R₁₅ is trialkylsilyl wherein thealkyls have from 1-4 carbon atoms; and R₁₆ is lower alkyl having 1 to 4carbon atoms.
 2. A compound of the formula: ##STR13## wherein R₁₄ islower alkyl having 1-6 carbon atoms; and R₁₅ is trialkylsilyl whereinthe alkyls have from 1-4 carbon atoms.
 3. A compound according to claim2 which is4-methyl-4(RS)-trimethylsilyloxy-oct-trans-1-enyl-tri-n-butyltin.
 4. Acompound of the formula: ##STR14## wherein R₁₄ is lower alkyl having 1-6carbon atoms; R₁₅ is an appropriate hydroxyl protecting group; and R₁₆is lower alkyl having 1 to 4 carbon atoms.